Neurodevelopmental defects in organoids with ANG mutation
2024
University of Bath, Bath, United Kingdom
Mutations in Angiogenin (ANG) and TARDBP are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. The researchers obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. They reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress were investigated. Multiple striking neurodevelopmental defects were observed. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. The findings may indicate that subtle developmental defects play a role in disease susceptibility or onset.
Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin
Vasanta Subramanian
Added on: 04-02-2024
[1] https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6244[2] https://www.drugtargetreview.com/news/113539/neurodevelopmental-defects-seen-in-mini-brains-with-ang-mutation/
